Pyrazole

Endpoint summary

Description of key information

oral
28 d, rat, drinking water: NOAEL = 1.5 mg/kg bw in males; 1.9 mg/kg bw in females (due to reduced water consumption, mild anemia, leukocytosis, slight impairment of hepatocellular and renal function, increased synthesis rate of serum proteins and cholesterol, substance-related changes in thyroid and spleen in higher doses; GLP, OECD 407, BASF 1998) 
28 d, rat, gavage: NOAEL = 6.8 mg/kg bw (due to body weight reduction, hematological findings, increased weights and gross changes of the thyroid, liver testis and seminal vesicles and microscopic changes in the thyroid, testis, prostate, seminal vesicles, bone marrow and spleen found in the higher dose; Magnusson et al. 1972)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

1.5 mg/kg bw/day

Additional information

In a GLP conform drinking water study according to OECD guideline 407, groups of male and female Wistar rats received 20, 100 or 600 ppm of the test substance (purity unknown) for 4 weeks, followed by a recovery period of 2 weeks. The groups consisted of 13 animals per sex in the control and high dose treatment and of 8 animals per sex in the other treatments. The 20, 100 and 600 ppm values corresponds to 1.5, 7.3 and 38.9 mg/kg bw in males and 1.9, 9.2 and 84.0 mg/kg bw in females, respectively.

In high dose treatment, following effects were observed: impairment of the food and water consumption and of the food efficiency; reduced body weight, mild anemia, leukocytosis, slight impairment of hepatocellular and renal function, increased synthesis rate of serum proteins and cholesterol, substance-related changes in thyroid and spleen. In the mid dose, slight impairment of water consumption in males, increases in total protein, albumin, globulins and cholesterol in the males, increases in platelets and thyroid stimulating hormone (TSH) in the females, decreases in hemoglobin and triglycerides in the females and increased extramedullary hematopoiesis in the spleen of male and female rats were observed. In the low dose, no substance related effects were observed. In the recovery period, the effects were not fully reversible in animals of the high dose treatment. Therefore, the NOAEL is identified as 20 ppm corresponding to 1.5 mg/kg bw in males and 1.9 mg/kg in females (BASF 1998).

In a subchronic study with male and female rats, animals received the test substance (purity unknown) in doses of 35 -38 mg/kg bw in sucrose daily for 8 to 23 weeks per gavage. The treatment resulted in a retardation of growth but not in any microscopical liver damage. Even after 23 weeks, daily doses of 35 mg/kg only led to the appearance of a few fat droplets in single scattered liver cells and some multinucleated hepatocytes. A NOAEL was not identified (Lelbach et al. 1969).

In a subacute study with rats, animals received the test substance (purity unknown) in doses of 6.8 or 68 mg/kg bw daily for 4 weeks per gavage. The most important clinical sign was a strongly retarded body weight gain among rats in the high dose group. Further, in these animals significantly decreased values for packed cell volume, hemoglobin and number of erythrocytes were recorded. Gross changes were observed in the thyroid, liver, testis and seminal vesicles. The thyroid was 2 to 3 times larger than normal. The liver was enlarged, while the testes were diminished having somewhat less than half of the normal weight. The seminal vesicles were slightly to moderately diminished. Microscopic changes due to the test substance were found in the thyroid, testis, prostate, seminal vesicles, bone marrow and spleen. In the thyroid there was a hyperplasia in the form of an interfollicular adenomatosis. The testis showed an atrophia with regressive changes of the epithelium. The tubules were diminished and the spermatogenous epithelium displayed vacuolization, desquamation and necrobiotic nuclear changes. The interstitial tissue was oedematous. Atrophic changes appeared in the prostate and seminal vesicles. In the bone marrow there was a slightly to moderately reduced cellularity suggesting a depletion of cells. Based on the reported results, a NOAEL of 6.8 mg/kg bw could be identified (Magnusson et al. 1972).

In another subacute study with rats, animals received the test substance (purity unknown) daily in mainly unknown doses for 2 or 4 weeks. Toxicity in rats consisted of bloody diarrhea, red discoloration of tears, partial alopecia, and brown scaly changes in the skin. The lethal dose was 150 mg/kg/day, at which time slight to moderate anemia and moderate leukopenia occurred in 2 of 4 rats; no thrombocytopenia was noted. At doses below this level, only slight anemia occurred and after a 4 -week recovery period the rats were normal hematologically. Gross findings in rats at autopsy revealed mottling of the liver and decrease in the size of the spleen in the animals receiving a higher dosage level. A NOAEL could not be identified (Wilson and Bottiglieri 1972).

In a subacute study with rats, animals received the test substance (purity unknown) in a doses of 64.8 mg/kg bw daily for 24 days per gavage. The treatment retarded growth and resulted also in a striking increase of liver weight. There was a parallel rise of total liver protein, but no change in total liver fat and DNA activities of MEOS, as well as of pentobarbital and benzypyrene hydroxylases, were significantly reduced. Aniline hydroxylase activity was not significantly affected. Serum bilirubin increased slightly but significantly. Serum glucose was moderately although significantly decreased. Conspicuous hepatic alterations were observed both by light and by electron microscopy. Some fat droplets appeared, strictly limited to the central zones. The smooth endoplasmic reticulum was increased and vesicular, whereas parallel arrays of rough endoplasmic reticulum were scarce. Mitochondria were enlarged and distorted. Bile canaliculi appeared normal. A NOAEL could not be identified (Lieber et al. 1970).

In a further subacute study with rats, animals received 50 mg/kg bw of the test substance (purity unknown) daily 6 days per gavage. The treatment caused a 40 % decrease in rat serum dopamine ß-hydroxylase (DBH) activity. Ethanol given simultaneously with the test substance prevented the inhibition. 4 -Hydroxypyrazole, the major metabolite of the test substance, competitively inhibited both rat serum DBH and partially purified bovine adrenal DBH in vitro. In vivo, 4-hydroxypyrazole caused large decreases in rat serum (53 -84 %) and adrenal (97 %) DBH activity but had no effect on brain enzyme. The decrease in rat serum DBH after subacute treatment and the pyrazole induced changes in physiological parameters, such as body weight and temperature, may be due to the formation of 4 -hydroxypyrazole. A NOAEL could not be identified (Harralson et al. 1978).

Justification for classification or non-classification

According to the test results from subacute studies, the test substance Pyrazole has the potential for the danger of serious damage to health by prolonged exposure if swallowed (R 48/22 according 67/548/EEC requirements and STOT-repeated dose Cat. 1 according to GHS requirements, respectively).